Metalloproteinases, including matrix metalloproteinase (MMP), (human fibroblast) collagenase, gelatinase and TNF convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-9611209, WO-A-9712902 and WO-A-9719075, the contents of which are incorporated herein by reference. MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the adamalysin family (or ADAMs) whose members include TNF convertase (TACE) and ADAM-10, which can cause the release of TNF.alpha. from cells, and others, which have been demonstrated to be expressed by human articular cartilage cells and also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown, such as collagenase, stromelysin and gelatinase, have been shown to inhibit the release of TNF both in vitro and in vivo. See Gearing et al (1994), Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561; GB-A-2268934; and WO-A-9320047. All of these reported inhibitors contain a hydroxamic acid zinc-binding group, as do the imidazole-substituted compounds disclosed in WO-A-9523790. Other compounds that inhibit MMP and/or TNF are described in WO-A-9513289, WO-A-9611209, WO-A-96035687, WO-A-96035711, WO-A-96035712 and WO-A-96035714.
WO-A-9718188 discloses MMP inhibitors of the formula EQU Ph.sup.1 -Ph.sup.2 --X--(CH.sub.2).sub.0-6 (CZ).sub.0-1 --(CHR.sup.1).sub.0-1 --CO--NHOH
wherein Ph.sup.1 and Ph.sup.2 are each optionally-substituted phenyl; X is absent, O, NH or S; Z is --CONR.sup.2 R.sup.3 ; and R.sup.1 is H, alkyl, alkenyl, OH, optionally-substituted phenylalkyl or phenyl-SO.sub.0-2 -alkyl, or alkyl-COOR.sup.1.
EP-A-0780386 discloses compounds having MMP and TNF inhibitory activity, of the formula EQU Y--CO--CR.sup.1 R.sup.2 --CR.sup.3 --S(O).sub.n R.sup.5
wherein n is 0, 1 or 2; Y is OH or NHOH; R.sup.1 is H or lower alkyl; R.sup.2 is H, lower alkyl, heteroalkyl, aryl, aralkyl, arylheteroalkyl, cycloalkyl, heteroaryl, heteroaralkyl, heteroarylheteroalkyl, heterocyclo, heterocyclo-lower alkyl, heterocyclo-lower heteroaryl or NR.sup.6 R.sup.7 ; R.sup.3 is H, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl or lower alkoxy, R.sup.4 is H, lower alkyl, cycloalkyl or cycaloalkylalkyl; and R.sup.5 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.
Compounds of EP-A-0780386 first disclosed in U.S. application Ser. No. 8939, filed Dec. 20, 1995, are of the same formula, wherein R.sup.1 is H; R.sup.2 is H, lower alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclo or NR.sup.6 R.sup.7 ; R.sup.3 is H, lower alkyl, cycloalkyl, cycloalkylalkyl or aralkyl; R.sup.4 is H or lower alkyl; and R.sup.5 is lower alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.
U.S. Pat. No. 4,325,964 discloses certain benzhydryl sulphinyl hydroxamates, as having utility in neuopsychic ailments.
Zayed et al, Zeitschrift fur Naturforschung (1966) 180-182, discloses 3-phenylsulphonylpropanoic acid N-hydroxyamide, as a fungicide.